Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with an incidence of about 20% in adults 65 years of age increasing to 37% in individuals 75 years or older. Non-exudative AMD is characterized by drusen accumulation and atrophy of rod and cone photoreceptors in the outer retina, retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris; while exudative AMD leads to choroidal neovascularization (Green and Enger, Ophthalmol, 100:1519-35, 1993; Green et al., Ophthalmol, 92:615-27, 1985; Green and Key, Trans Am Ophthalmol Soc, 75:180-254, 1977; Bressler et al., Retina, 14:130-42, 1994; Schneider et al., Retina, 18:242-50, 1998; Green and Kuchle (1997). In: Yannuzzi, L. A., Flower, R. W., Slakter, J. S. (Eds.) Indocyanine green angiography. St. Louis: Mosby, p. 151-6). Retinitis pigmentosa (RP) represents a group of hereditary dystrophies characterized by rod degeneration with secondary atrophy of cone photoreceptors and underlying pigment epithelium. (Pruett, Trans Am Ophthalmol Soc, 81:693-735, 1983; Heckenlively, Trans Am Ophthalmol Soc, 85:438-470, 1987; Pagon, Sur Ophthalmol, 33:137-177, 1988; Berson, Invest Ophthalmol Vis Sci, 34:1659-1676, 1993; Nickells and Zack, Ophthalmic Genet, 17:145-65, 1996). The pathogenesis of retinal degenerative diseases such as AMD and RP is multifaceted and can be triggered by environmental factors in normal individuals or in those who are genetically predisposed. To date more than 100 genes have been mapped or cloned that may be associated with various outer retinal degenerations.
Light exposure is an environmental factor that has been identified as a contributing factor to the progression of retinal degenerative disorders such as AMD (Young, Sur Ophthal, 32:252-269, 1988; Taylor, et al., Arch Ophthal, 110:99-104, 1992; Cruickshank, et al., Arch Ophthal, 111:514-518, 1993). Photo-oxidative stress leading to light damage to retinal cells has been shown to be a useful model for studying retinal degenerative diseases for the following reasons: damage is primarily to the photoreceptors and retinal pigment epithelium (RPE) of the outer retina, the same cells that are affected in heredodegenerative diseases (Noell et al., Invest Ophthal Vis Sci, 5, 450-472, 1966; Bressler et al., Sur Ophthal, 32, 375-413, 1988; Curcio et al., Invest Ophthal Vis Sci, 37, 1236-1249, 1996); apoptosis is the cell death mechanism by which photoreceptor and RPE cells are lost in AMD and RP, as well as following a photo-oxidative induced cell injury (Ge-Zhi et al., Trans AM Ophthal Soc, 94, 411-430, 1996; Abler et al., Res Commun Mol Pathol Pharmacol, 92, 177-189, 1996; Nickells and Zack, Ophthalmic Genet, 17:145-65, 1996); light has been implicated as an environmental risk factor for progression of AMD and RP (Taylor et al., Arch Ophthalmol, 110, 99-104, 1992; Naash et al., Invest Ophthal Vis Sci, 37, 775-782, 1996); and therapeutic interventions which inhibit photo-oxidative injury have also been shown to be effective in animal models of heredodegenerative retinal disease (LaVail et al., Proc Nat Acad Sci, 89, 11249-11253, 1992; Fakforovich et al., Nature, 347, 83-86, 1990; Frasson et al., Nat. Med. 5, 1183-1187, 1990).
A number of different compound classes have been identified in various animal models that minimize retinal photo-oxidative injury. They include: antioxidants such as ascorbate (Organisciak et al., Invest Ophthal Vis Sci, 26:1589-1598, 1985), dimethylthiourea (Organisciak et al., Invest Ophthal Vis Sci, 33:1599-1609, 1992; Lam et al., Arch Ophthal, 108:1751-1752, 1990), α-tocopherol (Kozaki et al., Nippon Ganka Gakkai Zasshi, 98:948-954, 1994) and β-carotene (Rapp et al., Cur Eye Res, 15:219-232, 1995); calcium antagonists such as flunarizine (Li et al., Exp Eye Res, 56: 71-78, 1993; Edward et al., Arch Ophthal, 109, 554-622, 1992; Collier et al., Invest Ophthal Vis Sci, 36:S516); growth factors such as basic-fibroblast growth factor, brain derived nerve factor, ciliary neurotrophic factor, and interleukin-1-β (LaVail et al., Proc Nat Acad Sci, 89, 11249-11253, 1992); glucocorticoids such as methylprednisolone (Lam et al., Graefes Arch Clin Exp Ophthal, 231, 729-736, 1993) and dexamethasone (Fu et al., Exp Eye Res, 54, 583-594, 1992); iron chelators such as desferrioxamine (Li et al., Cur Eye Res, 2, 133-144, 1991); NMDA-antagonists such as eliprodil and MK-801 (Collier et al., Invest Ophthal Vis Sci, 40:S159, 1999).
Serotonergic 5-HT1A agonists (i.e., buspirone, ziprasidone, urapidil) have either been registered or launched for the treatment of anxiety, hypertension, schidzophrenia, psychosis or depression-bipolar disorders. In addition, 5-HT1A agonists have been shown to be neuroprotective in various animal models and are being evaluated in the clinic to treat cerebral ischemia, head trauma, Alzheimer's Disease, Multiple Sclerosis and amytrophic lateral sclerosis. The 5-HT1A agonists, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) and ipsapirone, were shown to prevent NMDA-induced excitotoxic neuronal damage in the rat magnocellular nucleus basalis (Oosterink et al., Eur J Pharmacol, 358:147-52, 1998), dosing with Bay-x-3702 significantly reduced ischemic damage in a rat acute subdermal hematoma model (Alessandri et al., Brain Res, 845:232-5, 1999), while 8-OH-DPAT, Bay-x-3702, urapidil, gepirone and CM 57493 significantly reduced cortical infarct volume in the rat (Bielenberg and Burkhardt, Stroke, 21(Suppl): IV161-3; Semkova et al., Eur J Pharmacol, 359:251-60, 1998; Peruche et al., J Neural Transm—Park Dis Dement Sect, 8:73-83, 1994) and mouse (Prehn et al., Eur J Pharmacol, 203:213-22, 1991; Prehn et al., Brain Res, 630:10-20, 1993) after occlusion of the middle cerebral artery. In addition, treatment of rats with SR 57746A, a potent 5-HT1A agonist, has been shown to be neuroprotective following 4-vessel transient global ischemia, vincristine sulphate induced septohippocampal lesions, acrylamide-induced peripheral neuropathy, and sciatic nerve crush (Fournier et al., Neurosci, 55:629-41, 1993) and has been shown to delay the progression of motor neuron degeneration in pmn mice (Fournier et al., Br J Pharmacol, 124:811-7, 1998).
This class of compounds has been disclosed for the treatment of glaucoma (lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al) and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol. 210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT) (a 5-HT1A agonist) reduces IOP in rabbits. Wang, et al. (Current Eye Research, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488, March, 1998) disclose that 5-methylurapidil, an α1A antagonist and 5-HT1A agonist lowers IOP in the monkey, but due to its α1A receptor activity. Also, 5-HT1A antagonists are disclosed as being useful for the treatment of glaucoma (elevated IOP) (e.g. WO 92/0338, McLees). Furthermore, DeSai, et al. (WO 97/35579) and Macor, et al. (U.S. Pat. No. 5,578,612) disclose the use of 5-HT1 and 5-HT1-like agonists for the treatment of glaucoma (elevated IOP). These anti-migraine compounds are 5-HT1B,D,E,F agonists, e.g., sumatriptan and naratriptan and related compounds.